10.1002/cmdc.201900538
ChemMedChem
CDCl3) δ 166.60, 156.95, 152.67, 133.16, 127.93, 125.30, 125.22, 121.55, 117.70, 110.93, 55.65,
46.40, 36.76, 35.61, 25.76, 24.44, 24.06, 22.06, 20.69, 20.24. LC-MS (ESI) m/z found: 367
[M+H]+; retention time: 4.55 minutes. HRMS-ESI [M+H]+ calculated for C21H27N4O2: 367.2129,
found 367.2116.
(4aS,8aR)-4-(3-bromo-4-methoxyphenyl)-2-(cyclobutylmethyl)-4a,5,6,7,8,8a-
hexahydrophthalazin-1(2H)-one (33)
Phthalazinone 13 (450 mg, 1.33 mmol) was dissolved in DMF (10 mL) and sodium hydride (60%
in mineral oil) (59 mg, 1.5 mmol) was added. The mixture was stirred for 15 min after which
(bromomethyl)cyclobutane (0.18 mL, 1.6 mmol) was added and the mixture was stirred for another
16 h. The reaction was quenched pouring the mixture in water (50 mL) and the aqueous layer was
extracted with MTBE (50 mL). The organic layer was washed with sat. aqueous NaHCO3 (2x 50
mL) and brine (50 mL) after which the organic layer was dried over Na2SO4. The solids were
filtered off and volatiles were evaporated in vacuo after which the remaining crude was purified
over SiO2 using a gradient of 10% EtOAc in heptane towards 70% EtOAc in heptane yielding 430
mg (1.06 mmol, 79%) of the title compound as a white solid. 1H-NMR: (500 MHz, CDCl3) δ 7.97
(d, J = 2.1 Hz, 1H), 7.66 (dd, J = 8.6, 2.1 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 4.13 (dd, J = 13.2, 7.7
Hz, 1H), 3.93 (s, 3H), 3.65 (dd, J = 13.2, 7.1 Hz, 1H), 3.05 – 2.95 (m, 1H), 2.75 (h, J = 7.8 Hz,
1H), 2.70 – 2.64 (m, 1H), 2.59 – 2.49 (m, 1H), 2.07 – 1.97 (m, 2H), 1.93 – 1.76 (m, 5H), 1.69 –
1.59 (m, 3H), 1.45 – 1.23 (m, 5H). 13C-NMR: (126 MHz, CDCl3) δ 167.17, 156.74, 151.27, 130.83,
128.89, 126.20, 112.11, 111.47, 56.37, 53.30, 36.40, 35.96, 26.12, 26.09, 25.71, 24.40, 23.95,
22.00, 18.46. LC-MS (ESI) m/z found: 405 [M+H]+; retention time: 5.91 minutes. HRMS-ESI
[M+H]+ calculated for C20H26BrN2O2: 405.1172, found 405.1165.
(4aS,8aR)-2-(cyclobutylmethyl)-4-(4-methoxy-3-(1H-pyrazol-4-yl)phenyl)-4a,5,6,7,8,8a-
hexahydrophthalazin-1(2H)-one (38)
Phthalazinone 33 (150 mg, 0.37 mmol) and (1H-pyrazol-4-yl)boronic acid (62 mg, 0.56 mmol)
were added to a microwave tube with a stirring bean, subsequently DME (4 ml) and 1M sodium
carbonate (2 mL, 2.0 mmol) were added and the mixture was degassed for 5 min with N2. After
addition of PdCl2(dppf).CH2Cl2 (30 mg, 0.037 mmol) the mixture was degassed for another 2
minutes and the vessel was sealed and heated for 1 h at 120oC. The mixture was diluted with
EtOAc (25 mL), filtered over Celite and the organic layer was washed with water (2x 25 mL) and
brine (25 mL). The organic layer was dried over Na2SO4, solids were filtered off and the residue
was concentrated in vacuo. Remaining crude was purified over SiO2 using a gradient of 50%
heptanes in EtOAc towards 5% MeOH in EtOAc to yield 37 mg (0.09 mmol, 25%) of the title
compound as an off-white solid. 1H-NMR: (500 MHz, CDCl3) δ 8.09 (s, 2H), 8.00 (d, J = 1.8 Hz,
1H), 7.59 (dd, J = 8.6, 2.0 Hz, 1H), 6.97 (d, J = 8.7 Hz, 1H), 4.17 (dd, J = 13.2, 7.6 Hz, 1H), 3.94
(s, 3H), 3.68 (dd, J = 13.2, 7.1 Hz, 1H), 3.14 – 3.03 (m, 1H), 2.82 – 2.68 (m, 2H), 2.61 – 2.51 (m,
13
1H), 2.12 – 1.97 (m, 2H), 1.94 – 1.76 (m, 5H), 1.73 – 1.59 (m, 2H), 1.50 – 1.29 (m, 4H). C-
NMR: (126 MHz, CDCl3) δ 167.35, 157.02, 152.87, 133.38, 127.59, 125.35, 125.22, 121.77,
117.58, 110.94, 105.69, 55.63, 53.25, 36.47, 36.12, 34.86, 26.20, 25.78, 24.55, 24.02, 22.08, 18.52.
LC-MS (ESI) m/z found: 393 [M+H]+; retention time: 4.83 minutes. HRMS-ESI [M+H]+
calculated for C23H28N4O2: 393.2285, found 393.2276.
21
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